Keloids result from aberrant and overly exuberant wound healing and represent a significant cosmetic problem for affected individuals. We propose to expand currently a funded parent grant (ROIAR56672-01, Pharmacology of Dermal Fibrosis) to examine the pathophysiology of keloids in response to NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Our current research is centered on determining the role of adenosine A2, receptors in the pathogenesis of fibrosis using mouse models and in vitro studies of normal dermal fibroblasts. We have previously demonstrated a significant role for these receptors in the pathogenesis of dermal and hepatic fibrosis and found evidence supporting multiple pathways of signal transduction. We propose here two complementary aims designed to study the pathogenesis of fibrosis in keloids. In the first aim we will explore the role of adenosine A2A receptors in the pathogenesis of keloids. Thus, our first aim is: To determine the number and function of adenosine receptors in keloidal fibroblasts. Using standard molecular and pharmacologic techniques we will study the effect of adenosine A2A and A2B receptor stimulation on signaling intermediates (cAMP), messages for stimulation of collagen production (flil levels in the nucleus and CTGF expression) and collagen production (mRNA and protein). In Aim II we propose: To explore the hypothesis that adenosine or other growth factor receptors signal for aberrant protein expression in keloidal fibroblasts. Because it is possible that either aberrant adenosine signaling or aberrant signaling at growth factor receptors in keloidal fibroblasts (CTGF and TGFI3) may playa role in the pathogenesis of keloids we will study the effect of adenosine and growth factor stimulation on gene expression in normal and keloidal fibroblasts by microarray analysis of mRNA and smRNA. The results of the proposed experiments will shed light on aberrant signaling in keloidal fibroblasts and thus provide novel targets for therapeutic development in the treatment and prevention of keloids.